US5254537A - Composition and treatment with peptide combinations - Google Patents

Composition and treatment with peptide combinations Download PDF

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US5254537A
US5254537A US07/711,183 US71118391A US5254537A US 5254537 A US5254537 A US 5254537A US 71118391 A US71118391 A US 71118391A US 5254537 A US5254537 A US 5254537A
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peptide
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magainin
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Michael Zasloff
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Childrens Hospital of Philadelphia CHOP
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Assigned to CHILDREN'S HOSPITAL OF PHILADELPHIA, THE A PA NON-PROFIT CORPORATION reassignment CHILDREN'S HOSPITAL OF PHILADELPHIA, THE A PA NON-PROFIT CORPORATION ASSIGNS THE ENTIRE INTEREST MICHAEL A. ZASLOFF DOES HEREBY CONSENTS TO SAID ASSIGNMENT. Assignors: MAGAININ SCIENCES, INC., A CORP. OF DE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates

Definitions

  • This invention relates to biologically active peptides, and more particularly to compositions and uses involving combinations of biologically active peptides.
  • a composition which includes (a) a magainin peptide or analogue or derivative thereof; and (b) at least one member selected from the group consisting of (i) a PGLa peptide or analogue or derivative thereof and (ii) an XPF peptide or analogue or derivative thereof.
  • the magainin peptide or analogue or derivative thereof, as well as the PGLa peptide or analogue or derivative thereof and the XPF peptide or analogue or derivative thereof may be amide terminated or carboxy-terminated.
  • a process which comprises administering to a host both (a) a magainin peptide or analogue or derivative thereof and (b) at least one member selected from the group consisting of (i) an XPF peptide or analogue or derivative thereof and (ii) a PGLa peptide or analogue or derivative thereof.
  • components (a) and (b) may be administered in separate compositions.
  • components (a) and (b) may be administered in a single composition.
  • components (a) and (b) may be administered in amounts effective to inhibit growth of a target.
  • the target for example, may be bacteria, fungi, protozoa, virally infected cells, malignant cells, or sperm cells as compared to normal host cells.
  • the synergism may be due to association of the peptides to a novel multimeric complex, such as a dimer, which possesses markedly increased membrane affinity for the target cells.
  • the complex formed between the two peptides is believed to possess potent membrane disruptive properties. It is believed that the peptides have the capacity to organize within target cell membranes and to disturb cellular functions.
  • the magainin peptide or analogue or derivative thereof is employed in a dosage of from about lmg to about 100 mg per kilogram of host weight, when administered systemically.
  • the magainin peptide is used in a concentration of from about 0.5% to about 0.50%.
  • the PGLa peptide or analogue or derivative thereof when administered systemically, is administered in a dosage of from about 1 mg to about 100 mg per kilogram of host weight. When administered topically, the PGLa peptide is administered in a concentration of from about 0.5% to about 0.50%.
  • the XPF peptide or analogue or derivative thereof when administered systemically, is administered in a dosage of from about 1 mg to about 100 mg per kilogram of host weight. When administered topically, the XPF peptide or analogue or derivative thereof is administered in a concentration of from about 0.05% to about 0.50%.
  • this combination of peptides in accordance with the present invention is effective as an antibiotic, and may be employed to inhibit, prevent or destroy the growth or proliferation of microbes, such as bacteria, fungi, or the like.
  • such compositions may be employed as an anti-viral composition to inhibit, prevent or destroy the growth or proliferation of viruses or virally-infected cells.
  • compositions may also be employed as a spermicide to inhibit, prevent or destroy the motility of sperm.
  • compositions may also be employed as anti-tumor agents to inhibit the growth of or destroy tumors.
  • compositions have a broad range of potent antibiotic activity against a plurality of microorganisms, including gram-positive and gram-negative bacteria, fungi, protozoa and the like. Such compositions may be employed for treating or controlling microbial infection caused by organisms which are sensitive to such composition.
  • the treatment may comprise administering to a host organism or tissues acceptable to or affiliated with a microbial infection an anti-microbial amount of magainin peptide or analog or derivative thereof and of PGLa peptide or XPF peptide.
  • compositions may also be used as preservatives or sterilants for materials susceptible to microbial contamination.
  • the magainin peptide may be, for example, a magainin such as magainin I, II or III or an analogue or derivative thereof.
  • the magainin peptides preferably include the following basic peptide structure X 12
  • R 11 is a hydrophobic amino acid
  • R 12 is a basic hydrophilic amino acid
  • R 13 is a hydrophobic, neutral hydrophilic or basic hydrophilic amino acid
  • R 14 and R 14a are hydrophobic or or a hydrophobic or basic hydrophilic amino acid
  • n is 0 or 1.
  • R 13 is a hydrophobic or neutral hydrophilic amino acid
  • R 14a is a hydrophobic amino acid
  • R 15 is glutamic acid or aspartic acid.
  • the hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Val, Trp, and Tyr.
  • the neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, and Thr.
  • the basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, and His, Orn, homoarginine (Har), 2,-4-diaminobutyric acid, and p-aminophenylalamine.
  • the magainin peptides generally include preferably at least seventeen amino acids and may also include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
  • a magainin peptide may include the following structure:
  • R 11 , R 12 , R 14 and R 14a are as previously defined.
  • a magainin peptide may also have the following structure
  • R 16 where R 16 is a basic hydrophilic amino acid or asparagine or glutamine.
  • R 17 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid.
  • R 17 is a neutral hydrophilic amino acid.
  • a magainin peptide may also have the following structure:
  • X 12 , Y 12 and Z 12 are as previously defined and a is 0 or 1 and b is 0 or 1.
  • the magainin peptides may also include the following basic peptide structure X 13 :
  • R 11 , R 12 , R 13 , R 14 , and R 14a are amino acids as hereinabove described.
  • the magainin peptide may also include the following structure X 13 --Z 13 ; wherein X 13 is the hereinabove described basic peptide structure and Z 13 is
  • R 11 , R 14 , R 14a , R 15 , R 16 , and R 17 are as hereinabove described, and n is 0 or 1, and each n may be the same or different.
  • the magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids.
  • a magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
  • magainin peptides having the following primary sequences as given in the accompanying sequence listing as well as appropriate analogues and deriatives thereof:
  • Magainin peptides are described in Proc. Natl. Acad Sci. Vol 84 pp. 5449-53 (Aug. 87).
  • magainin peptides refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analogs.
  • the peptide employed in conjunction with the magainin peptide is a PGLa peptide or an XPF peptide.
  • a PGLa peptide is either PGLa or an analogue or derivative thereof.
  • the PGLa peptides preferably include the following basic structure X 14 : ##STR1## where R 11 , R 12 , R 14 , and R 17 are as previously defined.
  • the PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide sturcture for a PGLa peptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.
  • a PGLa peptide may have the following sturcture:
  • R 11 and R 14 are as previously defined.
  • a PGLa peptide may also have the following structure:
  • a PGLa peptide may also have the following structure:
  • X 14 ; Y 14 and Z 14 are as previously defined, a is 0 or and b is 0 or 1.
  • An XPF peptide is either XPF or an analogue or derivative thereof.
  • the XPF like peptides preferably include the following basis peptide structure X 16 : ##STR2## wherein R 11 , R 12 ,R 14 ,R 15 and R 17 are as previously defined and R 18 is glutamine or asparagine, or a basic hydrophilic, or hydrophobic amino acid, and n is 0 or 1.
  • the XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
  • an XPF peptide may include the following structure:
  • R 11 and R 14 are as previously defined.
  • An XPF peptide may include the following structure:
  • An XPF peptide may also have the following structure:
  • X 16 , Y 16 and Z 16 are as previously defined: a is 0 or 1 and b is 0 or 1.
  • XPF or PGLa peptides which are characterized by the following primary amino acid sequences as given in the accompanying sequence listing:
  • MGN2 Magainin 2
  • PGLa peptide a mixture of MGN2 and PGLa in a 1:1 molar ratio was added to the broth in increasing concentration.
  • MIC minimal inhibitory concentration
  • the concentration of S. aureus killed by 100 ⁇ g/ml of preparations of Magainin 2, PGLa, and a preparation of Magainin 2 and PGLa in a 1:1 molar ratio is noted. It was found that a 100 ⁇ g/ml preparation of Magainin 2 does not completely kill S. aureus at concentrations of bacteria at less than 10 bacterial/ml. Similar results were also obtained for PGLa.
  • the 100 ⁇ g/ml preparation of the equimolar miture of Magainin 2 and PGLa achieved complete killing of a concentration of 10 5 bacteria/ml.
  • the equimolar mixture of Magainin 2 and PGLa achieved an increase in bactericidal potency over either peptide by greater than 10 5 .
  • peptide combinations in accordance with the present invention, may be employed for treating a wide variety of hosts.
  • a host may be an animal, and such animal may be a human or non-human animal.
  • the magainin peptide and the PGLa and/or XPF peptide may be employed together in a single composition, or in separate compositions.
  • the magainin peptide and PGLa and/or XPF peptide may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
  • Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. It is also contemplated that the magainin peptide and the PGLa and/or XPF peptide may be delivered or administered in different forms.
  • the magainin peptide and PGLa and/or XPF peptide may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses, and the like.
  • the peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or a spermicidal amount.

Abstract

A composition comprising a magainin peptide or an analogue or derivative thereof, and at least one member selected from the group consisting of a PGLa peptide or analogue or derivative thereof, and an XPF peptide or analogue or derivative thereof. The composition is employed as a pharmaceutical.

Description

This application is a continuation-in-part of Application Ser. No. 346,894, filed May 3, 1989, now abandoned which is a continuation-in-part of Application Ser. No. 302,985, filed Jan. 30, 1989 now abandoned.
This invention relates to biologically active peptides, and more particularly to compositions and uses involving combinations of biologically active peptides.
In accordance with an aspect of the present invention, there is provided a composition which includes (a) a magainin peptide or analogue or derivative thereof; and (b) at least one member selected from the group consisting of (i) a PGLa peptide or analogue or derivative thereof and (ii) an XPF peptide or analogue or derivative thereof. The magainin peptide or analogue or derivative thereof, as well as the PGLa peptide or analogue or derivative thereof and the XPF peptide or analogue or derivative thereof, may be amide terminated or carboxy-terminated.
In accordance with another aspect of the present invention, there is provided a process which comprises administering to a host both (a) a magainin peptide or analogue or derivative thereof and (b) at least one member selected from the group consisting of (i) an XPF peptide or analogue or derivative thereof and (ii) a PGLa peptide or analogue or derivative thereof. In one embodiment, components (a) and (b) may be administered in separate compositions. In another embodiment, components (a) and (b) may be administered in a single composition. In addition, components (a) and (b) may be administered in amounts effective to inhibit growth of a target.
Although the present invention is not to be limited by any theoretical reasoning, it is believed that the combination of the magainin peptide with the PGLa peptide or XPF peptide provides a synergistic effect in the inhibition of growth of a target. The target, for example, may be bacteria, fungi, protozoa, virally infected cells, malignant cells, or sperm cells as compared to normal host cells. The synergism may be due to association of the peptides to a novel multimeric complex, such as a dimer, which possesses markedly increased membrane affinity for the target cells. The complex formed between the two peptides is believed to possess potent membrane disruptive properties. It is believed that the peptides have the capacity to organize within target cell membranes and to disturb cellular functions.
In general, the magainin peptide or analogue or derivative thereof is employed in a dosage of from about lmg to about 100 mg per kilogram of host weight, when administered systemically. When administered topically, the magainin peptide is used in a concentration of from about 0.5% to about 0.50%.
The PGLa peptide or analogue or derivative thereof, when administered systemically, is administered in a dosage of from about 1 mg to about 100 mg per kilogram of host weight. When administered topically, the PGLa peptide is administered in a concentration of from about 0.5% to about 0.50%.
The XPF peptide or analogue or derivative thereof, when administered systemically, is administered in a dosage of from about 1 mg to about 100 mg per kilogram of host weight. When administered topically, the XPF peptide or analogue or derivative thereof is administered in a concentration of from about 0.05% to about 0.50%.
The use of this combination of peptides in accordance with the present invention is effective as an antibiotic, and may be employed to inhibit, prevent or destroy the growth or proliferation of microbes, such as bacteria, fungi, or the like. Similarly, such compositions may be employed as an anti-viral composition to inhibit, prevent or destroy the growth or proliferation of viruses or virally-infected cells.
Such compositions may also be employed as a spermicide to inhibit, prevent or destroy the motility of sperm.
Such compositions may also be employed as anti-tumor agents to inhibit the growth of or destroy tumors.
The compositions have a broad range of potent antibiotic activity against a plurality of microorganisms, including gram-positive and gram-negative bacteria, fungi, protozoa and the like. Such compositions may be employed for treating or controlling microbial infection caused by organisms which are sensitive to such composition. The treatment may comprise administering to a host organism or tissues acceptable to or affiliated with a microbial infection an anti-microbial amount of magainin peptide or analog or derivative thereof and of PGLa peptide or XPF peptide.
The compositions may also be used as preservatives or sterilants for materials susceptible to microbial contamination.
The magainin peptide may be, for example, a magainin such as magainin I, II or III or an analogue or derivative thereof. The magainin peptides preferably include the following basic peptide structure X12 
--R.sub.11 --R.sub.11 --R.sub.12 --R.sub.13 --R.sub.11 --R.sub.14 --R.sub.12 --R.sub.11 --R.sub.14 --R.sub.12 --R.sub.11 --R.sub.11 --R.sub.11 --R.sub.14a --(R.sub.15).sub.n --R.sub.14a --R.sub.14 --
wherein R11 is a hydrophobic amino acid, R12 is a basic hydrophilic amino acid; R13 is a hydrophobic, neutral hydrophilic or basic hydrophilic amino acid; R14 and R14a are hydrophobic or or a hydrophobic or basic hydrophilic amino acid, and n is 0 or 1. In a preferred embodiment, R13 is a hydrophobic or neutral hydrophilic amino acid, R14a is a hydrophobic amino acid, and R15 is glutamic acid or aspartic acid.
The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Val, Trp, and Tyr. The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, and Thr. The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, and His, Orn, homoarginine (Har), 2,-4-diaminobutyric acid, and p-aminophenylalamine.
The magainin peptides generally include preferably at least seventeen amino acids and may also include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
Thus, for example, a magainin peptide may include the following structure:
--Y.sub.12 --X.sub.12 --
where X12 is the hereinabove described basic peptide structure and Y12 is
(i) R12
ii) R14a --R12
(iii) R11 --R14a --R12
(iv) R14 --R11 --R14a --R12
wherein R11, R12, R14 and R14a are as previously defined.
A magainin peptide may also have the following structure
--X.sub.12 --Z.sub.12 --
wherin X12 is as previously defined and Z12 is:
(i) R16 where R16 is a basic hydrophilic amino acid or asparagine or glutamine.
(ii R16 --R17 where R17 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid. Preferably R17 is a neutral hydrophilic amino acid.
A magainin peptide may also have the following structure:
(Y.sub.12) a--X.sub. 12 (Z.sup.12).sub.b
where X12, Y12 and Z12 are as previously defined and a is 0 or 1 and b is 0 or 1.
The magainin peptides may also include the following basic peptide structure X13 :
--R.sub.14 --R.sub.11 --R.sub.14a --R.sub.12 --R.sub.11 --R.sub.11 --R.sub.12 --R.sub.13 --R.sub.11 --R.sub.14 --R.sub.12 --R.sub.11 --R.sub.11 --R.sub.12 --,
wherein R11, R12, R13, R14, and R14a are amino acids as hereinabove described.
The magainin peptide may also include the following structure X13 --Z13 ; wherein X13 is the hereinabove described basic peptide structure and Z13 is
(R.sub.11).sub.n --(R.sub.11).sub.n --(R.sub.11).sub.n --(R.sub.14a).sub.n --(R.sub.15).sub.n --(R.sub.14a) .sub.n --(r.sub.14).sub.n --R.sub.16).sub.n --(R.sub.17) .sub.n
wherein R11, R14, R14a, R15, R16, and R17 are as hereinabove described, and n is 0 or 1, and each n may be the same or different.
The magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids. A magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequences as given in the accompanying sequence listing as well as appropriate analogues and deriatives thereof:
(a) (NH2) (SEQ ID NO:1) (OH) or (NH2) (Magainin I)
(b) (NH2) (SEQ ID NO:2) (OH) or (NH2) (Magainin II)
(c) (NH2) (SEQ ID NO:3) (OH) or (NH2) (Magainin III)
The following are examples of peptide derivatives or analogues of the basic structure:
(d) (NH2) (SEQ ID NO:4) (OH) or (NH2)
(e) (NH2) (SEQ ID NO:5) (OH) or (NH2)
(f) (NH2) (SEQ ID NO:6) (OH) or (NH2)
Magainin peptides are described in Proc. Natl. Acad Sci. Vol 84 pp. 5449-53 (Aug. 87). The term "magainin peptides" as used herein refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analogs.
The peptide employed in conjunction with the magainin peptide is a PGLa peptide or an XPF peptide.
A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic structure X14 : ##STR1## where R11, R12, R14, and R17 are as previously defined.
The PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide sturcture for a PGLa peptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.
Thus, for example, a PGLa peptide may have the following sturcture:
--Y.sub.14 --X.sub.14 --
where X14 is as previously defined and
Y14 is
(i) R11 ;
(ii) R14 --R11
where R11 and R14 are as previously defined.
For example, a PGLa peptide may also have the following structure:
--X.sub.14 --Z.sub.14 --
where X14 is as previously defined; and Z14 is:
(i) R11 ; or
(ii) R11 --R11, where R11 is as previously defined.
A PGLa peptide may also have the following structure:
(Y.sub.14).sub.a --X.sub.14 --(Z.sub.14 (.sub.b
where X14 ; Y14 and Z14 are as previously defined, a is 0 or and b is 0 or 1.
An XPF peptide is either XPF or an analogue or derivative thereof. The XPF like peptides preferably include the following basis peptide structure X16 : ##STR2## wherein R11, R12,R14,R15 and R17 are as previously defined and R18 is glutamine or asparagine, or a basic hydrophilic, or hydrophobic amino acid, and n is 0 or 1.
The XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
Thus, for example, an XPF peptide may include the following structure:
--Y.sub.16 --X.sub.16 --
where X16 is as previously defined and Y16 is
(i) R11 or
(ii) R14 --R11
where R11 and R14 are as previously defined.
An XPF peptide may include the following structure:
--X.sub.16 --Z.sub.16 --
where X16 is as previously defined and Z16 is
(i) R11 ; or
(ii) R11 --R18 ; or
(iii) R11 --R18 -Proline; or
(iv) R11 --R18 -Proline --R12
An XPF peptide may also have the following structure:
(Y.sub.16).sub.a --X.sub.16 ) (Z.sub.16).sub.b
where X16, Y16 and Z16 are as previously defined: a is 0 or 1 and b is 0 or 1.
Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequences as given in the accompanying sequence listing:
PGLa: (SEQ ID NO:7) (NH2)
XPF: (SEQ ID NO:8)
A review of XPF and PGLa can be found in Hoffman et al, EMBO J. 2:711-714, 1983; Andreu et al, J. Biochem. 149:531-535, 1985; Gibson et al J. Biol. Chem. 261:5341-5349, 1986; and Giovanni et al, Biochem J. 241:113-120, 1987.
The present invention will be further described with respect to the following examples, however, the scope of the present invention is not to be limited thereby.
EXAMPLE 1
About 105 bacteria/ml were added to a small volume of Luria broth. Magainin 2 (MGN2), PGLa peptide, or a mixture of MGN2 and PGLa in a 1:1 molar ratio was added to the broth in increasing concentration. The minimal inhibitory concentration (MIC), which inhibits microbial growth completely at 24 hours is noted below in Table 1.
              TABLE 1                                                     
______________________________________                                    
ANTIBACTERIAL ACTIVITY OF                                                 
COMBINATION OF PGLa AND MAGAININ 2                                        
         MINIMAL INHIBITORY                                               
         CONCENTRATION (μg/ml)                                         
                               PGLa/MGN2                                  
ORGANISM   MGN2       PGLa     (1:1 molar ratio)                          
______________________________________                                    
S. aureus  >500       >500     10                                         
P. aeruginosa                                                             
           250        250      10                                         
C. albicans                                                               
           250        240      10                                         
Micrococcus                                                               
           125        125      10                                         
Diphtheroids                                                              
           125        125      10                                         
E. coli     50         50      10                                         
______________________________________
The above results indicate an increase in antibacterial activity when a combination of Magainin 2 and PGLa peptides is added to a culture broth of bacteria in a 1:1 molar ratio of Magainin 2 to PGLa over either peptide added alone.
EXAMPLE 2
In this example, the concentration of S. aureus killed by 100 μg/ml of preparations of Magainin 2, PGLa, and a preparation of Magainin 2 and PGLa in a 1:1 molar ratio is noted. It was found that a 100 μg/ml preparation of Magainin 2 does not completely kill S. aureus at concentrations of bacteria at less than 10 bacterial/ml. Similar results were also obtained for PGLa. The 100 μg/ml preparation of the equimolar miture of Magainin 2 and PGLa, however, achieved complete killing of a concentration of 105 bacteria/ml. Thus, the equimolar mixture of Magainin 2 and PGLa achieved an increase in bactericidal potency over either peptide by greater than 105.
EXAMPLE 3
Approximately 103 S aureus bacteria were added per/ml of Luria broth. Peptide preparations containing varying molar ratio amounts of PGLa to Magainin 2 (mole PGLa/mole MGN2) were added to the broths to increasing concentration of peptide (μg/ml). The microbial inhibitory concentration (MIC), at which point no growth was evident after 24 hours was measured for each peptide preparation. The results are given in Table 2 below.
              TABLE 2                                                     
______________________________________                                    
Mole PGLa/                                                                
Mole MGN2    MIC vs. S. aureus (μg/ml)                                 
______________________________________                                    
10/0         >500                                                         
10/1         25                                                           
7.5/2.5      15                                                           
5/5           8                                                           
2.5/7.5      15                                                           
 1/10        25                                                           
 0/10        >500                                                         
______________________________________
The above results indicate that maximum bactericidal activity is achieved when an equimolar mixture of PGLa and Magainin 2 is added to the S. aureus culture. It is also shown, however, that preparations containing both peptides in any molar ratio achieved greater bactericidal activity than either peptide alone.
The peptide combinations, in accordance with the present invention, may be employed for treating a wide variety of hosts. In accordance with a preferred embodiment, a host may be an animal, and such animal may be a human or non-human animal. The magainin peptide and the PGLa and/or XPF peptide may be employed together in a single composition, or in separate compositions.
The magainin peptide and PGLa and/or XPF peptide may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution. Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. It is also contemplated that the magainin peptide and the PGLa and/or XPF peptide may be delivered or administered in different forms. The magainin peptide and PGLa and/or XPF peptide may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa, viruses, and the like.
The peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or a spermicidal amount.
Numerous modifications and variations of the present invention are possible in light of the above teachings, and, therefore, within the scope of the accompanying claims, the invention may be practiced other than as particularly described.
__________________________________________________________________________
SEQUENCE LISTING                                                          
(1) GENERAL INFORMATION:                                                  
(iii) NUMBER OF SEQUENCES: 8                                              
(2) INFORMATION FOR SEQ ID NO:1:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 23 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: Magainin I peptide.                                         
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Zasloff, Michael                                             
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
(D) VOLUME: 84                                                            
(F) PAGES: 5449-5453                                                      
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
(I) FILING DATE: 04-MAR-1987                                              
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                   
GlyIleGlyLy sPheLeuHisSerAlaGly                                           
510                                                                       
LysPheGlyLysAlaPheValGlyGluIle                                            
1520                                                                      
MetLysSer                                                                 
(2) INFORMATION FOR SEQ ID NO:2:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 23 amino acids                                                
(B) TYPE: amino acid                                                      
 (D) TOPOLOGY: linear                                                     
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: Magainin II peptide.                                        
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Zasloff, Michael                                             
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
(D) VOLUME: 84                                                            
(F) PAGES: 5449-5453                                                      
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
 (I) FILING DATE: 04-MAR-1987                                             
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                   
GlyIleGlyLysPheLeuHisSerAlaLys                                            
510                                                                       
LysPheGlyLysAlaPheValGlyGluIle                                            
1520                                                                      
MetAsnSer                                                                 
( 2) INFORMATION FOR SEQ ID NO:3:                                         
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 22 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: Magainin III peptide.                                       
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Zasloff, Michael                                             
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
 (D) VOLUME: 84                                                           
(F) PAGES: 5449-5453                                                      
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
(I) FILING DATE: 04-MAR-1987                                              
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                   
GlyIleGlyLysPheLeuHisSerAlaLys                                            
510                                                                       
LysPheGlyLys AlaPheValGlyGluIle                                           
1520                                                                      
MetAsn                                                                    
(2) INFORMATION FOR SEQ ID NO:4:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 22 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: magainin peptide.                                           
(x) PUBLICATION INFORMATION:                                              
 (A) AUTHORS: Zasloff, Michael                                            
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
(D) VOLUME: 84                                                            
(F) PAGES: 5449-5453                                                      
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
(I) FILING DATE: 04-MAR-1987                                              
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                   
IleGlyLysPheLeuH isSerAlaLysLys                                           
510                                                                       
PheGlyLysAlaPheValGlyGluIleMet                                            
1520                                                                      
AsnSer                                                                    
(2) INFORMATION FOR SEQ ID NO:5:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 21 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
 (ii) MOLECULE TYPE: peptide                                              
(ix) FEATURE:                                                             
(A) NAME/KEY: magainin peptide.                                           
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Zasloff, Michael                                             
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
(D) VOLUME: 84                                                            
(F) PAGES: 5449-5453                                                      
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
(I) FILING DATE: 04-MAR-1987                                              
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                   
GlyLysPheLeuHisSerAlaLysLysPhe                                            
510                                                                       
GlyLysAlaPheValGlyGluIleMetAsn                                            
1520                                                                      
Ser                                                                       
(2) INFORMATION FOR SEQ ID NO:6:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 20 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: magainin peptide.                                           
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Zasloff, Michael                                             
(C) JOURNAL: Proceedings of the National Academy                          
of Sciences                                                               
(D) VOLUME: 84                                                            
(F ) PAGES: 5449-5453                                                     
(G) DATE: AUG - 1987                                                      
(H) DOCUMENT NUMBER: US 4810777                                           
(I) FILING DATE: 04-MAR-1987                                              
(J) PUBLICATION DATE: 07-MAR- 1989                                        
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                   
LysPheLeuHisSerAlaLysLysPheGly                                            
510                                                                       
LysAlaPheValGlyGluIleMetAsnS er                                           
1520                                                                      
(2) INFORMATION FOR SEQ ID NO:7:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 21 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: PGLa peptide.                                               
(x) PUBLICATION INFORMATION:                                              
(A) AUTHORS: Hoffman, et al.                                              
(C) JOURNAL: EMBO J.                                                      
 (D) VOLUME: 2                                                            
(F) PAGES: 711-714                                                        
(G) DATE: 1983                                                            
(A) AUTHORS: Andreu, et al.                                               
(C) JOURNAL: Journal of Biochemistry                                      
(D) VOLUME: 149                                                           
(F) PAGES: 531-535                                                        
(G) DATE: 1985                                                            
(A) AUTHORS: Gibson, et al.                                               
(C) JOURNAL: J. Biol. Chem.                                               
(D) VOLUME: 261                                                           
 (F) PAGES: 5341-5349                                                     
(G) DATE: 1986                                                            
(A) AUTHORS: Giovannini, et al.                                           
(C) JOURNAL: Biochem J.                                                   
(D) VOLUME: 243                                                           
(F) PAGES: 113-120                                                        
(G) DATE: 1987                                                            
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                   
GlyMetAlaSerLysAlaGlyAlaIleAla                                            
510                                                                       
 GlyLysIleAlaLysValAlaLeuLysAla                                           
1520                                                                      
Leu                                                                       
(2) INFORMATION FOR SEQ ID NO:8:                                          
(i) SEQUENCE CHARACTERISTICS:                                             
(A) LENGTH: 25 amino acids                                                
(B) TYPE: amino acid                                                      
(D) TOPOLOGY: linear                                                      
(ii) MOLECULE TYPE: peptide                                               
(ix) FEATURE:                                                             
(A) NAME/KEY: XPF peptide.                                                
 (x) PUBLICATION INFORMATION:                                             
(A) AUTHORS: Hoffman, et al.l                                             
(C) JOURNAL: EMBO J.                                                      
(D) VOLUME: 2                                                             
(F) PAGES: 711-714                                                        
(G) DATE: 1983                                                            
(A) AUTHORS: Andreu, et al.                                               
(C) JOURNAL: Journal of Biochemistry                                      
(D) VOLUME: 149                                                           
(F) PAGES: 531-535                                                        
(G) DATE: 1985                                                            
(A) AUTHORS: Gibson, et al.                                               
(C) JOURNAL: J. Biol. Chem.                                               
(D) VOLUME: 261                                                           
(F) PAGES: 5341-5349                                                      
(G) DATE: 1986                                                            
(A) AUTHORS: Giovannini, et al.                                           
(C) JOURNAL: Biochem J.                                                   
(D) VOLUME: 243                                                           
(F) PAGES: 113-120                                                        
(G) DATE: 1987                                                            
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                   
GlyTrpAlaSerLysI leGlyGlnThrLeu                                           
510                                                                       
GlyLysIleAlaLysValGlyLeuLysGlu                                            
1520                                                                      
LeuIleGlnProLys                                                           
25

Claims (26)

What is claimed is:
1. A composition comprising:
a) a magainin peptide, sequence ID. No. 1, 2, or 3, or analogue or derivative thereof, sequence ID No. 4,5, or 6; and
(b) at least one member selected from the group consisting of (i) a PGLa peptide, sequence ID. No. 7 and (ii) an XPF peptide, sequence ID. No. 8.
2. The composition of claim 1 wherein components (a) and (b) are present in an amount effective to inhibit growth of a target cell, wherein the said target cell is a bacterium, a fungus, or a protozoan.
3. The compositions of claim 1 wherein component (b) is a PGLa peptide, sequence ID. No. 7.
4. The composition of claim 1, wherein component (b) is an XPF peptide, sequence ID. No. 8.
5. The composition of claim 2, wherein each of components (a) and (b) is present in an amount effective to inhibit growth of a target cell, which is less than if each component were administered alone to a host wherein the said target cell is a bacterium, a fungus, or a protozoan.
6. A process for inhibiting growth of a target cell, in a host wherein the said target cell is a bacterium, a fungus, or a protozoan, comprising: administering to a host both (a) a margainin peptide, sequence ID. No. 1, 2, or 3, analogue or derivative thereof, sequence ID. No. 4, 5, or 6, and (b) at least one member selected from the group consisting of (i) an XPF peptide, sequence ID. No. 8 or and (ii) a PGLa peptide, sequence ID. No. 7, wherein components (a) and (b) are present in amounts effective to inhibit growth of a target cell, virus, or virally-infected cell in a host.
7. The process of claim 6 wherein components (a) and (b) are administered in separate compositions.
8. The the process of claim 6 wherein (a) and (b) are administered in a single composition.
9. The process of claim 6 wherein the magainin peptide, sequence ID. No. 1, 2, or 3, analogue or derivative thereof, sequence ID. No. 4, 5, or 6, is administered systemically.
10. The process of claim 9 wherein the magainin peptiede, sequence ID. No. 1, 2, or 3, analogue or derivative thereto, sequence ID. No. 4, 5, or 6, is administered in an amount of from about 1 mg to about 100 mg per kilogram of host body weight.
11. The process of claim 6 wherein the magainin peptide, sequence ID. No. 1, 2, or 3, analogue or derivative thereof, sequence ID. No. 4, 5, or 6, is administered topically.
12. The process of claim 11 wherein the magainin peptide, sequence ID. No. 1, 2, or 3, analogue or derivative thereof, sequence ID. No. 4, 5, or 6, is administered in a concentration of from about 0.05 % to about 0.50% by weight.
13. The process of claim 6 wherein component (b) is a PGLa peptide, sequence ID. No. 7.
14. The process of claim 13 wherein the PGLa peptide, sequence ID. No. 7 is administered systemically.
15. The process of claim 14 wherein the PGLa peptide, sequence ID. No. is administered in an amount of from about 1 mg to about 100 mg per kilogram of host body weight.
16. The process of claim 13 wherein the PGLa peptide, sequence ID. No. is administered topically.
17. The process of claim 16 wherein the PGLa peptide or analogue or derivative thereof is administered in a concentration of from about 0.05% to about 0.050% by weight.
18. The process of claim 6 wherein component (b) is an XPF peptide, sequence ID. No. 8.
19. The process of claim 18 wherein the XPF peptide is administered systemically.
20. The process of claim 19 wherein the XPF peptide, sequence ID. No. 8 is administered in an amount of from about 1 mg to about 100 mg per kilogram of host body weight.
21. The process of claim 18 wherein the XPF peptide, sequence ID. No. 8 is administered topically.
22. The process of claim 21 wherein the XPF peptide, sequence ID. No. 8 is administered in a concentration of from about 0.05% to about 0.50% by weight.
23. The process of claim 6 wherein said target cell is a bacterium.
24. The process of claim 6 wherein said target cell is a fungus.
25. The process of claim 6 wherein said target cell is a protozoan.
26. The process of claim 6 wherein each of components (a) and (b) is administered in an amount effective to inhibit growth of a target cell, which is less than if each component were administered alone to a host wherein the said target cell is bacterium, a fungus or a protozoan.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519115A (en) * 1991-02-01 1996-05-21 Enichem S.P.A. Reverse antimicrobial peptides
US5734015A (en) * 1995-06-19 1998-03-31 Magainin Pharmaceuticals Inc. Family of linear antimicrobial peptides from hagfish intestine
WO1999006564A1 (en) * 1997-07-31 1999-02-11 Sanford Scientific, Inc. Expression of antimicrobial peptide genes in plants, and their use in creating resistance to multiple plant pathogens
US6348445B1 (en) 1992-06-01 2002-02-19 Magainin Pharmaceuticals, Inc. Biologically active peptides with reduced toxicity in animals and a method for preparing same

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
Andreu et al., J. Biochem. 149:531 535, 1985. *
Andreu et al., J. Biochem. 149:531-535, 1985.
Gibson et al., "Novel Peptide Fragments Originating from PGLa and the Caeruleinand Xenopsin Precursors from Xenopus laevis," J. Biol. Chem. 261:5341-5349, 1986.
Gibson et al., Novel Peptide Fragments Originating from PGLa and the Caeruleinand Xenopsin Precursors from Xenopus laevis, J. Biol. Chem. 261:5341 5349, 1986. *
Giovannini, et al., "Biosynthesis and degradation of peptides derived from Xenopus laevis prohormones," Biochem. J. 243:113-120, 1987.
Giovannini, et al., Biosynthesis and degradation of peptides derived from Xenopus laevis prohormones, Biochem. J. 243:113 120, 1987. *
M. Zasloff, "Magainins, a class of antimicrobial peptides from Xenopus skin: Isolation, characterization of two active forms, and partial cDNA sequence of a precursor," Proc. Natl. Acad. Sci., vol. 84, pp. 5449-5453 (Aug. 1987).
M. Zasloff, Magainins, a class of antimicrobial peptides from Xenopus skin: Isolation, characterization of two active forms, and partial cDNA sequence of a precursor, Proc. Natl. Acad. Sci., vol. 84, pp. 5449 5453 (Aug. 1987). *
W. Hoffmann et al., "A novel peptide designated PYLa and its precursor as predicted from cloned mRNA of Xenopus laevis skin," EMBO J. 2:711-714, 1983.
W. Hoffmann et al., A novel peptide designated PYLa and its precursor as predicted from cloned mRNA of Xenopus laevis skin, EMBO J. 2:711 714, 1983. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519115A (en) * 1991-02-01 1996-05-21 Enichem S.P.A. Reverse antimicrobial peptides
US6348445B1 (en) 1992-06-01 2002-02-19 Magainin Pharmaceuticals, Inc. Biologically active peptides with reduced toxicity in animals and a method for preparing same
US5734015A (en) * 1995-06-19 1998-03-31 Magainin Pharmaceuticals Inc. Family of linear antimicrobial peptides from hagfish intestine
WO1999006564A1 (en) * 1997-07-31 1999-02-11 Sanford Scientific, Inc. Expression of antimicrobial peptide genes in plants, and their use in creating resistance to multiple plant pathogens
US6235973B1 (en) 1997-07-31 2001-05-22 Sanford Scientific, Inc. Expression of magainin and PGL classes of antimicrobial peptide genes in plants, and their use in creating resistance to multiple plant pathogens
AU739960B2 (en) * 1997-07-31 2001-10-25 Sanford Scientific, Inc. Expression of antimicrobial peptide genes in plants, and their use in creating resistance to multiple plant pathogens

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